Absorbing agents and cover layer which is impermeable to active substances and which contains channel-formers or removable protective layer of a transdermal therapeutic system

ABSTRACT

This present invention concerns a cover layer that is impermeable to the active substances and/or a removable protective layer of a transdermal therapeutic system, comprising a thermoplastic film which either directly contains the absorbing agents and channel-forming agents or is coated with a polymer support (thermoplast) containing these substances. The polymer support can either be applied over the entire surface of the film or in patterns, directly during production. The thermoplastic film that is used and the polymer support can be made from either the same or different materials.

This present invention concerns a cover layer that is impermeable to theactive substances or a removable protective layer of a transdermaltherapeutic system containing absorbing agents and channel-formingagents.

BACKGROUND AND SUMMARY OF THE INVENTION

The cover layers used in conventional transdermal therapeutic systemsare films made from acetal, acrylate, acrylonitrile butadiene styrene,acrylonitrile (methyl methacrylate) copolymer, acrylonitrile copolymer,ethylene ethyl acrylate, ethylene methyl acrylate, ethylene vinylacetate, ethylene vinyl acetate copolymer, ethylene vinyl alcoholpolymer, ionomers, nylon (polyamide), nylon copolymer, polybutylene,polycarbonate, polyester, polyethylene terephthalate, thermoplasticpolyester copolymer, polyethylene copolymer (high-density), polyethylene(high molecular weight, high-density), polyethylene (intermediatemolecular weight, high-density), polyethylene (linear low-density),polyethylene (low density), polyethylene (medium density), polyethyleneoxide, polyimide, polypropylene, polypropylene (coated), polypropylene(oriented), polystyrene, polyurethane, polyvinyl acetate, polyvinylchloride, polyvinylidene chloride, and/or styrene acrylonitrile, which,if required, may have been metallized or pigmented. They serve tostabilize the active substance-containing system and protect it againstexternal influences. The cover layer is impermeable to the activesubstances and therefore prevents the active substance from diffusing tothe outside.

The removable protective layers that are used in transdermal therapeuticsystems are also impermeable to the active substances and are usuallymade from polyester, polyethylene, polypropylene, polysiloxane,polyacrylate, ethylene vinyl acetate, polyurethane, polyisobutene orpaper, in most cases coated with silicon and/or polyethylene, or acomposite of these. They also serve to stabilize the activesubstance-containing system and protect it against external influences.The removable protective layer is impermeable to the active substancesand therefore prevents the active substance from diffusing to theoutside during storage.

Transdermal therapeutic systems are usually packaged in sachets. Thesachets are usually made from a laminate material coated with aluminum.Such coating increases the impermeability to humidity and oxygen of thepackaging. Permeability depends on the thickness of the coating. As thethickness of the aluminum coating increases, environmentalincompatibility and the costs incurred in manufacturing and disposing ofthe packaging increases. In practice, however, total impermeability cannot be attained. For that reason, the transdermal therapeutic system isalways exposed to a certain degree of humidity. In addition, afterproduction, the transdermal therapeutic system releases a certain amountof residual humidity to the environment. To ensure suitable storagestability, in the sachet, an inlay can be placed which contains a dryingagent. As a result, however, the packaging of the transdermaltherapeutic system becomes more complicated and significantly moreexpensive. Highly odorous substances such as amines and polymer monomerswhich are released during storage from the active substance or thepressure-sensitive adhesive layer can not be eliminated at all or onlypartially by using this method.

The object of this present invention is to increase the storagestability of transdermal therapeutic systems by minimizing the negativeimpact of humidity, oxygen, free amines and/or free polymer monomers onthe stability of the transdermal therapeutic systems. At the same time,the transdermal therapeutic systems are to be manufactured byconventional means, without any complicated additional production steps,and packaging costs are to be reduced simultaneously.

Surprisingly, it has been possible to achieve the object of this presentinvention by using, as a cover layer that is impermeable to the activesubstances or as a removable protective layer of the transdermaltherapeutic system, a polymer in the form of a film which eitherdirectly contains the absorbing agents and channel-forming agents orwhich is coated with a polymer support containing these substances. Thecoating can be applied either over the entire surface of the film or inpatterns (e.g. in a grid pattern) directly during production.

The company Capitol Specialty Plastics holds several patent applications(WO 00/17259, WO 00/17260, WO 00/16884, WO 99/62697, WO 99/61856, WO98/39231, WO 99/61855, WO 00/17258, WO 99/63288, U.S. Pat. No.5,911,937) which claim polymers containing absorbing agents, releasingagents, channel-forming agents, etc. These polymers are mainly used toeliminate humidity from packages. They are either inlays that are placedin the packages, or the packages are lined therewith. The thickness ofthe inlays and coating films described is ≧400 μm. This isdisadvantageous insofar as these inlays or coatings require anadditional production step and represent another cost factor.

By using the cover layer and/or removable protective layer in accordancewith this present invention, the thickness of the aluminum coating ofthe packaging can be greatly reduced. This benefits the environment andreduces the costs of the packaging. The manufacturing process need notbe changed. Common state-of-the-art manufacturing processes can continueto be used. In addition, no additional drying element needs to be placedin the packaging. The manufacturing costs of the TTS can therefore besignificantly reduced.

DETAILED DESCRIPTION OF THE INVENTION

The transdermal therapeutic system (TTS) can be stored in a stablemanner over long periods of time. Even under extreme conditions, such asin the tropics, the transdermal therapeutic system can be stored withoutadditional elements for a prolonged period of time without a loss ofstability. Furthermore, TTS with humidity-sensitive active substancescan be stored without stability problems. In these cases, the storagetime can even be extended.

The cover layer that is impermeable to the active substances orremovable protective layer of a transdermal therapeutic system inaccordance with this present invention is made from a polymer, (i) whicheither contains the absorbing agents and channel-forming agentsdirectly, or (ii) is coated with a polymer support containing thesesubstances. The polymer support can be applied either over the entiresurface of the film or in patterns directly during production. In case aseparate polymer support is used, the cover layer and/or the protectivelayer and the polymer support can be made from either the same ordifferent materials.

The polymers used in the mixture of the polymer (for the polymer supportor the cover layer and/or the removable protective layers) may bepolyolefins, such as polyethylene and/or polypropylene, polyisoprenes,polybutadienes, polybutenes, polysiloxanes, polyamides, ethylene vinylacetate copolymers, ethylene methacrylate copolymers, polystyrenes,polyesters, polyanhydrides, polyacrylate nitrites, polysulfonates,polyesteramides, polyacrylate esters, propylene maleic anhydride,polyethylene maleic anhydride, polyethylene urethanes, polyethyleneethyl vinyl alcohols, polyethylene nylon, and/or polyurethanes.

Furthermore, the polymer may be a crosslinkable polymer which can becrosslinked by means of heat or radiation, in particular by means of UV.Therefore, the polymer of the polymer support or of the cover layerand/or of the removable protective layer can be crosslinkable. In case aseparate polymer layer is present, a thermally crosslinkable polymer canbe applied cold or under heat onto the cover layer and/or protectivelayer; a polymer that can be crosslinked under radiation can becrosslinked cold or hot. Crosslinking may be performed after therespective application.

The polymer content is 10–90 percent by weight based on the total weightof the mixture of the polymer, channel-forming agents, and absorbingagents, regardless of whether it is used directly as a film or as acoating.

The channel-forming agents used in this present invention can behydrophilic substances such as, for example, polyglycols, ethyl vinylalcohols, glycerin, pentaerythritol, polyvinyl alcohols, polyvinylpyrrolidone, vinyl pyrrolidone, N-methyl pyrrolidone, polysaccharides,saccharides, and/or sugar alcohols. As polyglycols, polyethylene glycoland/or polypropylene glycol are preferred. As saccharides, e.g. glucose,mannose, galactose, and/or fructose can be used. As sugar alcohols,mannitol, sorbitol, hexitol, dulcitol, xylitol, ribitol, and/or erythrolcan be used, among others. The term “polysaccharides” may mean, forexample, dextrines and/or hydrolyzed starch.

The content of the channel-forming agents can be 10–40 percent byweight, based on the total weight of the mixture of the polymer,channel-forming agents, and absorbing agents.

Different types of absorbing agents can be incorporated in the coverlayer or removable protective layer.

One embodiment of this present invention contains drying agents asabsorbing agents. There are three different types of drying agents.

One group contains chemical substances which form hydrates with water.Examples for such chemical substances are water-free salts which tend toabsorb water or humidity while forming a stable hydrate. During thisreaction, the humidity is retained, and its release as a result of achemical reaction is prevented.

The second group of drying agents contains reactive substances. Thesesubstances react with water or humidity by forming a new substance. Thenewly formed substances are normally stable at low temperatures. Theirformation can only be reversed by using high energy. This type of dryingagents is mainly used in drying solvents and as a water-absorbingmaterial in polymers which themselves need to remain in ahumidity-reduced state.

The third group of drying agents retains humidity by means of physicalabsorption. The drying agent particles have a fine capillary structure,as a result of which the humidity is drawn into these capillaries. Thepore size of the capillaries as well as the capillary density determinethe absorption properties of the drying agent. Examples for this type ofdrying agents include molecular sieves, silicon gels, earths (e.g.montmorillimite earth), certain synthetic polymers (e.g. polymers usedin baby diapers), and starches.

This group of drying agents is preferred due to its inertness and lackof solubility in water.

One preferred embodiment in accordance with this present inventioncontains, as a drying agent, molecular sieves with a pore size of 3–15Å.

Another embodiment in accordance with this present invention containssilicon gel with a pore size of 24 Å.

As other potential absorbing agents, metals and alloys, such as, forexample, nickel, copper, aluminum, silver and/or gold, metal-coatedparticles, such as, for example, silver-coated copper, silver-coatednickel and/or silver-coated glass microspheres, inorganic substances,such as, for example, barium titanium trioxide, strontium titaniumtrioxide, silicon dioxide, aluminum oxide, zinc oxide, titanium dioxide,manganese oxide, copper oxide, antimony oxide, molten silicon, amorphousmolten silicon, ion-exchange resins, lithium-containing metal oxides,hollow glass microspheres, silicon sol-gel, titanium sol-gel and/ormixed titanium, carbon-based substances, such as, for example, carbon,activated charcoal and/or diamond powder, elastomers, such as, forexample, polybutadiene and/or polysiloxanes, semi-metals, and/or ceramicmaterial can be used.

The content of the absorbing agent(s) can be 10 to 70 percent by weight,based on the total weight of the mixture of the polymer, channel-formingagents, and absorbing agents.

The content must not be too high since otherwise, the cover layerbecomes brittle. In case the content is too low, protection againsthumidity is not sufficient.

The absorbing agents incorporated in the polymer are uniformlydistributed in the polymer and/or the film. The channel-forming agentsincorporated in the polymer form channels which extend through theentire film and/or through the pattern that has been created from theoutside towards the inside. Oxygen, humidity, or other undesiredsubstances can therefore migrate from the outer environment into theinterior of the film and/or pattern and react with the absorbing agentsin the interior of the film and/or pattern. The absorption rate is manytimes higher since a larger number of absorbing agent particles canreact with the undesired substances than in the absence ofchannel-forming agents. Depending on which channel-forming agents areselected, finer and therefore a larger number of channels with increasedbranches or larger, less branched channels in a smaller number can becreated in the polymer. The finer the channels, the larger theabsorption rate for undesired substances.

If desired, pharmaceutically safe coloring agents can be added to themixture of the polymer, channel-forming agents, and absorbing agents.

In case the cover layer or removable protective layer is made from afilm with integrated channel-forming agents and absorbing agents, thethickness of the layer is 5–100 μm, in particular 15–40 μm, preferably15 μm.

In case the cover layer or removable protective layer is made from aconventional film, which, either over its entire surface or in apattern, has been coated with a mixture of the polymer, channel-formingagents, and absorbing agents, the thickness can be adjusted to anydesired value. The only factor which needs to be considered isflexibility. Flexibility must ensure satisfactory use of the transdermaltherapeutic system.

In accordance with this present invention, the film that isconventionally used for a cover layer that is impermeable to the activesubstances (4) can be coated with the mixture (5) on the top side and/orbottom side.

In accordance with this present invention, the film that isconventionally used for the removable protective layer can be coatedwith the mixture on the side facing outwards.

The term “transdermal therapeutic system” refers to a band (aid). Such aband may be a matrix or membrane system comprising a cover layer that isimpermeable to the active substances (4) and a removable protectivelayer (1). Both layers or only one of the layers can be provided withthe channel-forming agents and absorbing agents.

In case a separate polymer support is provided, for the removableprotective layer, polyester, polyethylene, polypropylene, polysiloxanes,polyacrylate, ethylene vinyl acetate, polyurethane, polyisobutene orpaper, in most cases coated with silicon and/or polyethylene, or acomposite can be used as conventional films.

In case a separate polymer support is provided, the cover layers used inconventional transdermal therapeutic systems can be used as films madefrom acetal, acrylate, acrylonitrile butadiene styrene, acrylonitrile(methyl methacrylate) copolymer, acrylonitrile copolymer, ethylene ethylacrylate, ethylene methyl acrylate, ethylene vinyl acetate, ethylenevinyl acetate copolymer, ethylene vinyl alcohol polymer, ionomers, nylon(polyamide), nylon (polyamide) copolymer, polybutylene, polycarbonate,polyester, polyethylene terephthalate, thermoplastic polyestercopolymer, polyethylene copolymer (high-density), polyethylene(high-molecular-weight, high-density), polyethylene(intermediate-molecular-weight, high-density), polyethylene (linearlow-density), polyethylene (low density), polyethylene (medium-density),polyethylene oxide, polyimide, polypropylene, polypropylene (coated),polypropylene (oriented), polystyrene, polyurethane, polyvinyl acetate,polyvinyl chloride, polyvinylidene chloride and/or styreneacrylonitrile, which, if needed, may be metallized or pigmented.

In accordance with one embodiment, the matrix band comprises the coverlayer that is impermeable to the active substances (4), one or severalself-adhesive matrix layer(s) (2) containing the active substance and/orpermeation-enhancing agents or one or several matrix layer(s) (13)coated with a pressure-sensitive adhesive (10), and a removableprotective layer (1).

For the matrix, the matrix-forming agents commonly used in medicine suchas polyacrylate, silicon, polyisobutylene, rubber, rubber-like synthetichomopolymers, copolymers or block polymers, butyl rubber,styrene/isoprene copolymerizate, polyurethanes, copolymers of ethylene,polysiloxanes, styrene/butadiene copolymerizate or a mixture thereof inaccordance with the state of the art are used.

As an adhesive, polydimethyl siloxane, polyacrylates, polyisobutylene,polyacrylate with C₄–C₁₀ alkyl alcohol esters, polyurethane, polyvinylether, amine-resistant silicon in ethyl acetate or n-heptane,polyisobutylene/mineral oil, or a mixture thereof can be used.

Another embodiment in accordance with this present invention representsa membrane system. Such system comprises the cover layer that isimpermeable to the active substances (4), an active substance-containingreservoir or a reservoir layer (12), a semipermeable membrane (11), anoptional pressure-sensitive adhesive (10), and a removable protectivelayer (1).

The reservoir contains the active substance(s) and/orpermeation-enhancing agents, stabilizing agents, emulsifiers, thickeningagents, and/or common adjuvants for membrane systems and/or reservoirbands. The reservoir and/or the reservoir layer is located between thecover layer and the membrane. As gelling agents, if needed, methylcellulose, hydroxypropyl cellulose, hydroxyl ethyl cellulose,carboxyvinyl polymer, sodium ply oxilate, carboxymethylcellulose, or amixture thereof can be used.

The membrane, which usually consists of inert polymers, in particular onthe basis of polypropylene, polyvinyl acetate, polyamide, ethylene vinylacetate copolymers and/or silicon, can have an effect controlling therelease of the active substance, depending on pore size.

For the pressure-sensitive adhesive layer, a pressure-sensitiveadhesive, for example on the basis of polyurethane, polyisobutylene,polyvinyl ether, silicon, polyacrylate, or a mixture thereof can bechosen.

The silicon-based adhesive may be a silicon adhesive based on two maincomponents: a polymer or adhesive, in particular polysiloxane, and anadhesiveness-increasing resin. The polysiloxane adhesive is usuallyprepared with a cross-linking agent for the adhesive, typically with ahighly molecular polydiorganosiloxane, as well as with the resin toproduce, by means of a suitable organic solvent, a three-dimensionalsilicate structure. Admixing the resin to the polymer is the mostimportant factor to modify the physical properties of the polysiloxaneadhesive; compare, for example, Sobieski, et al., “Silicone PressureSensitive Adhesives”, Handbook of Pressure Sensitive AdhesiveTechnology, 2^(nd) ed., pp. 508–517 (D. Satas, ed.), Van NostrandReinhold, New [Adhe]sive Technology, 2^(nd) ed., pp. 508–517 (D. Satas,ed.), Van Nostrand Reinhold, New York (1989).

Another example for a pressure-sensitive adhesive on a silicon basis istrimethylated silicon dioxide that has been treated with polydimethylsiloxane with trimethylsiloxy groups in the end position.

The adhesives on a polyacrylate basis can be any desired homopolymer,copolymer, or terpolymer consisting of different acrylic acidderivatives.

The polyacrylates may be polymers of one or several monomers of acrylicacids and other copolymerizable monomers. In addition, the acrylatepolymers can comprise copolymers of alkyl acrylates and/or methacrylatesand/or copolymerizable secondary monomers or monomers with functionalgroups. Once the quantity of each type that is added as a monomer ischanged, the cohesive properties of the resulting acrylate polymers canbe modified. In general, the acrylate polymer consists of at least 50percent by weight of an acrylate, methacrylate, alkyl acrylate or alkylmethacrylate monomer, 0 to 20% of a functional monomer, copolymerizablewith acrylate, and 0 to 50% of another monomer.

The following is a list of different acrylate monomers, such as, forexample, acrylic acid, methacrylic acid, butyl acrylate, butylmethacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate,isooctyl methacrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate,methyl acrylate, methyl methacrylate, 2-ethylhexyl acrylate,2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecylacrylate, dodecyl methacrylate, tridecyl acrylate, and tridecylmethacrylate, which can be polymerized alone or as a mixture.

In addition, functional monomers that are copolymerizable with the aboveacrylates, such as, for example, acrylic acid, methacrylic acid, maleicacid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate,acrylamide, dimethylacrylamide, acrylnitrile, dimethylaminoethylacrylate, dimethylaminoethyl methacrylate, tert. butylaminoethylacrylate, ter. butylaminoethyl methacrylate, methoxy ethyl acrylate,vinyl acetate, and methoxy ethyl methacrylate can be used in thecopolymerization.

Further details and examples for pressure-sensitive acrylates that aresuitable for this present invention are described in Satas Handbook ofPressure Sensitive Adhesive Technology “Acrylic Adhesives”, 2^(nd) ed.,pp. 396–456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).

The active substance contained in the transdermal therapeutic systemmay, for example, be a member of the group of active substances such ascorticoids, androgens, estrogens, gestagens, proton pump inhibitors,5-HT₁ antagonists, sympatholytic agents/sympathomimetic agents,anticholinergic agents, tranquilizers/anxiolytic agents, cessationagents, analgesics, calcium antagonists, antiemetics, vasodilators,opiate antagonists, coagulation inhibitors, Antiparkinson agents,antidementia agents/cholinesterase inhibitors, ACE inhibitors,antihistamine agents, ulcer therapy agents/H₂ receptor blockers,angiotensin II antagonists, neuroleptics, antidepressants, localanesthetics, and/or lipid reducers.

The transdermal therapeutic system may contain one or several members ofthe group of corticoids, such as beclomethasone, budesonide propionate,flunisolide acetate, triamcinolone, fluticasone,betamethasone-17-valerate, glycine acid, fluocortolone, beclomethasonedipropionate, budesonide base, dexamethasone, hydrocortisone,flunisolide, prednisone, triamcinolone acetonide, methylprednisolone,betamethasone, deflazacort, cortisone, cortisone acetate, prednylidene,cloprednol, fluocortolone-21-hexanoate, prednicarbate, and/or theirderivatives and/or their pharmaceutically safe salts, as a component ofthe active substance.

The transdermal therapeutic system may contain one or several members ofthe group of androgens, such as testosterone, testosterone undecanoate,androsterone, and/or their derivatives and/or their pharmaceuticallysafe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of estrogens, such as estradiol, estradiol benzoate, estradiolvalerate, estradiol dipropionate, estron, estriol, ethinyl estradiol,diethylstilbestrol, diethylstilbestrol dimethylether, diethylstilbestroldiphosphate, diethylstilbestrol dipropionate, and/or their derivativesand/or their other pharmaceutically safe salts, as a component of theactive substance.

The transdermal therapeutic system may contain one or several members ofthe group of gestagens, such as progesterone, cyproterone acetate,cyproterone, chlormadinone, chlormadinone acetate, medroxyprogesteroneacetate, levonorgestrel, norgestrel, norgestimate, norethisteroneacetate, and/or their derivatives and/or their other pharmaceuticallysafe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of proton-pump inhibitors, such as omeprazole, esomeprazole,lansoprazol, leminoprazole, pantoprazole, rabeprazole, polaprezinc,and/or their derivatives and/or their pharmaceutically safe salts, as acomponent of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of antimigraine agents and/or 5-HT₁ antagonists, such aslisuride, sumatriptan, sumatriptan hydrogen succinate, rizatriptan,rizatriptan benzoate, almotriptan, avitriptan, eletriptan, frovatriptan,naratriptan, zolmitriptan, and/or their derivatives, and/or their otherpharmaceutically safe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of sympatholytic agents/sympathomimetic agents, such asadimolol, adrenalin, albuterol, alprenolol, amosulalol, arotinolol,atenolol, bambuterol, betaxolol, bevantolol, bisoprolol, bitolterol,bopindolol, broxaterol, bucindolol, bucumolol, bufuralol, bunitrolol,bupranolol, butofilolol, carazolol, carbuterol, carteolol, carvedilol,cetamolol, cicloprolol, clenbuterol, cloranolol, carteolol,dihydroergotamine, dihydroergotamine tartrate, dihydroergotaminemesylate, dilevalol, doxazosin, etilefrine, epanolol, esatenolol,esmolol, fenetylline, fenoterol, formoterol, ibuterol, isoprenaline,labetalol, landiolol, levobetaxolol, levobunolol, levosalbutamol,mabuterol, mepindolol, metipranolol, metoprolol, morazone, nebivolol,nipradilol, norfenefrine, noradrenalin, oxprenolol, penbutolol,picumeterol, pimolol, pindolol, pirbuterol, phenmetrazine,phenylephrine, phentolamine, phenoxybenzamine, prazosine, procaterol,propanolol, rimiterol, reproterol, salbutamol, salmeterol, sotalol,sulfonterol, terazosin, terbutaline, tertatolol, tienoxolol, tilisolol,timolol, tolazoline, toliprolol, tolubuterol, tamsulosine, clonidine,moxonidine, and/or their derivatives and/or their pharmaceutically safesalts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of anticholinergic agents, such as ipratropium, oxitropium,atropine, scopolamine base, ipratropium bromide, oxitropium bromide,atropine methyl bromide, atropine methyl nitrate, atropine sulfate,atropine valerianate, scopolamine hydrobromide, scopolaminehydrochloride, scopolamine hydroiodide, tropicamide, oxybutinine, and/ortheir derivatives and/or their other pharmaceutically safe salts, as acomponent of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of tranquilizers/anxiolytic agents, such as alprazolam,bentazepam, bromazepam, camazepam, clorazepate, clonazepam, clotiazepam,diazepam, etiracetam, etizolam, fludiazepam, flunitrazepam, flurazepam,flutazolam, flutoprazepam, halazepami ketazolam, loprazolam, lorazepam,lormetazepam, medazepam, metaclazapam, mexazolam, midazolam, nitrazepam,norazepam, oxazepam, oxazolam, prazepam, temazepam, triazolam, and/ortheir derivatives and/or their pharmaceutically safe salts, as acomponent of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of cessation agents, such as nicotine, methadone, disulfirame,lobeline, and/or their derivatives and/or their pharmaceutically safesalts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of analgesics, such as ibuprofen, ketoprofen, alminoprofen,bermoprofen, carprofen, dexibuprofen, dexketoprofen, fenoprofen,flobufen, flunoxaprofen, flurbiprofen, loxoprofen, pelobiprofen,pranoprofen, pentazocine, tilnoprofen, ximoprofen, zaltroprofen,diclofenac, amfenac, bromfenac, clidanac, etodolac, felbinac, fentiazac,mofezolac, oxindanac, tifurac, indomethacin, acemetacin, piroxicam,ampiroxicam, meloxicam, isoxicam, lornoxicam, tenoxicam, butorphanolbuprenorphine, morphine, hydromorphone, dihydrocodeine, oxycodone,piritramide, pentazocine, levomethadone, tramadol, fentanyl, codeine,codeine hydrochloride, codeine phosphate, tilidine, tilidine mesylate,tilidine hydrochloride, diclofenac sodium, amfenac sodium, bromfenacsodium, clidanac sodium, etodolac sodium, felbinac sodium, fentiazacsodium, mofezolac sodium, oxindanac sodium, tifurac sodium, indomethacinsodium, acemetacin sodium, meloxicam cyclodextrin, buprenorphinehydrochloride, morphine acetate, hydromorphone hydrochloride, oxycodonehydrochloride, piritramide hydrogen tartrate, levomethadonehydrochloride, fentanyl dihydrogen citrate, and/or their derivativesand/or their other pharmaceutically safe salts, as a component of theactive substance.

The transdermal therapeutic system may contain one or several members ofthe group of calcium antagonists, such as amlodipine, arandipine,azelmidipine, barnidipine, benidipine, cilnidipine, efonidipine,felodipine, flordipine, iganidipine, isradipine, lacidipine,lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine,nisoldipine, nitrendipine, palonidipine, pranidipine, ticlopidine,vatanidipine, clentiazem, and/or their derivatives and/or theirpharmaceutically safe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of antiemetics, such as alizapride, azasetron, batanopride,clebopride, dazopride, dolasetron, domperidone, granisetron, itasetron,levosulpiride, metoclopramide, nabilone, ondansetron, pancopride,ramosetron, tropisetron, zatosetron, and/or their derivatives and/ortheir pharmaceutically safe salts, as a component of the activesubstance.

The transdermal therapeutic system may contain one or several members ofthe group of vasodilators, such as glycerol trinitrate (nitroglycerin),isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythrityltetranitrate, molsidomine, and/or their derivatives and/or their otherpharmaceutically safe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of opiate antagonists, such as naloxone, naltrexone, and/ortheir derivatives and/or their pharmaceutically safe salts, as acomponent of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of coagulation inhibitors, such as heparin sodium, certoparin,dalteparin, danaparoid, enoxaparin, nadroparin, reviparin, tinzaparin,heparinoid, warfarin, phenprocoumon, acenocoumarol, and/or theirderivatives and/or their pharmaceutically safe salts, as a component ofthe active substance.

The transdermal therapeutic system may contain one or several members ofthe group of Antiparkinson agents, such as aptiganel, biperiden,budipine, cabergoline, droxidopa, entacapone, idazoxan, lazabemide,milacemide, mofegiline, pergolide (pergolide mesylate, pergolidehydrochloride), pramipexole, quinelorane, rasagiline, remacemide,ropinorole, selegiline, talipexole, tolcapone, and/or their derivativesand/or their other pharmaceutically safe salts, as a component of theactive substance.

The transdermal therapeutic system may contain one or several members ofthe group of antidementia agents/cholinesterase inhibitors e.g.rivastigmine, neostigmine, physostigmine, pyridostigmine, donepezil,tacrine, and/or their derivatives and/or their other pharmaceuticallysafe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of ACE inhibitors, such as alacepril, benazepril, captopril,ceronapril, cilazapril, denapril, enalapril, enalapril maleate,fosinopril, imidapril, lisinopril, moexipril, moveltipril, perindopril,quinapril, ramipril, ramiprilat, ramipril mesylate, rentiapril,spirapril, temocapril, trandolapril, trandolapril mesylate, utibapril,zofenopril, and/or their derivatives and/or their other pharmaceuticallysafe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of antihistamine agents, such as acrivastine, astemizole,carebastine, cetirizine, descarbethoxy loratadine, dimethindene,ebastine, emedastine, epinastine, fexofenadine, ketotifen,levocabastine, loratadine, mequitazine, mizolastine, nafamostat,norastemizole, olopatidine, oxatomide, rupatadine, tazifylline,temelastine, traxanox, and/or their derivatives and/or their otherpharmaceutically safe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of ulcer therapy agents/H2 receptor blockers, such asdalcotidine, famotidine, lafutidine, niperdidine, nizatidine, osutidine,pibutidine, pirenzepine, ramixotidine, ranitidine, proglumide,misoprostol, and/or their derivatives and/or their pharmaceutically safesalts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of angiotensin II antagonists, such as candesartan,candesartan cilexetil, losartan, tasosartan, telmisartan, and/or theirderivatives and/or their pharmaceutically safe salts, as a component ofthe active substance.

The transdermal therapeutic system may contain one or several members ofthe group of neuroleptics, such as sulpiride, promethazine, benperidol,haloperidol, chlorprothixene, clozapine, fluphenazine, perphenazine,droperidol, pipamperone, prothipendyl, melperone, flupenthixoldecanoate, fluspirelene, bromperidol, levomepromazine hydrogen maleate,zotepine, pimozide, perazine, chlorpromethazine, triflupromethazine,risperidone, sertindole, amisulpride, olanzapine, zuclopenthixol,thioridazine, and/or their derivatives and/or their pharmaceuticallysafe salts, as a component of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of antidepressants, such as amitriptyline, clomipramine,maprotiline, doxepin, citalopram, fluvoxamine, reboxetine, alprazolam,fluoxetine, lofepramine, mianserin, and/or their derivatives and/ortheir pharmaceutically safe salts, as a component of the activesubstance.

The transdermal therapeutic system may contain one or several members ofthe group of local anesthetics, such as lidocaine, prilocaine,benzocaine, cocaine, procaine, tetracaine, bupivacaine, cinchocaine,etidocaine, mepivacaine, butanilicaine, levobupivacaine, ropivacaine,and/or their derivatives and/or their pharmaceutically safe salts, as acomponent of the active substance.

The transdermal therapeutic system may contain one or several members ofthe group of lipid reducers, such as colestyramine, xantinol nicotinate,fluvastatin, simvastatin, atorvastatin, pravastatin, cerivastatin,dalvastatin, itavastatin, lovastatin, dextrothyroxine sodium, and/ortheir derivatives and/or their pharmaceutically safe salts, as acomponent of the active substance.

The active substance contained in the transdermal therapeutic system,however, may also be leflunomide, indapamide, hydroxytamoxifen, fusidineacid, finasteride, tirofiban, rosiglitazone, pioglitazone, montelukast,and/or their derivatives and/or their pharmaceutically safe salts.

The term “pharmaceutically safe salts” of the above active substancesrefers to acid addition salts. They are obtained through the reaction ofthe active substance in the free form with pharmaceutically safe acids.Pharmaceutically safe acids are inorganic acids (e.g. muriatic acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) ororganic acids (e.g. acetic, propionic, hydroxy acetic, lactic, pyruvic,oxalic, maleic, malonic, succinic, fumaric, malic, tartaric, citric,methane sulfonic, ethane sulfonic, benzene sulfonic, p-toluene sulfonic,cyclohexane sulfamine, salicylic, p-amino salicylic and pamoic acid).The term “acid addition salts” also refers to solvates containing theactive substance. Such solvates include, for example, hydrates,alcoholates, and the like.

In terms of other potential, pharmaceutically safe salts of the aboveactive substances, mainly alkali metal and/or earth alkali metal saltsas well as the ammonium salt may be suited, such as, for example, thepotassium, sodium, lithium, calcium, magnesium, and ammonium salt.

As permeation-enhancing agents, optionally monovalent and/or plurivalentaliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols with up toeight C atoms each, e.g. ethanol, 1,2-propanediol, dexpanthenol and/orpolyethylene glycol; alcohol/water-mixtures; saturated and/orunsaturated fatty alcohols with 8–18 C atoms each; terpenes; e.g.cineol, carveol, menthone, terpineol, verbenone, menthol, limonene,thymol, cymene, terpinene-4-ol, neomenthol, geraniol, fenchone; mixturesof terpenes and ethanol and/or propylene glycol; tea tree oil; saturatedand/or unsaturated cyclic ketones; alkyl methyl sulfoxides; saturatedand/or unsaturated fatty acids with 8–18 C atoms each; their esters andsalts; natural vitamin E; synthetic vitamin E and/or vitamin Ederivatives; sorbitan fatty acid esters and ethoxylated sorbitan fattyacid esters; azones (laurocapram); azones mixed with alcohols;carbamide; 1-alkyl pyrrolidone; block copolymers of polyethylene glycoland dimethyl siloxanes with a cationic group at the end; isopropylmyristate, isopropyl palmitate, folate polyethylene glycol liposome,proliposome; polyoxyethylene-10-stearyl ether; a mixture ofpolyoxyethylene-10-stearyl ether and glyceryl dilaurate;dodecyl-2-(N,N-dimethylamino)-propanol tetradecanoate and/ordodecyl-2-(N,N-dimethylamino)-propianate; N-acetyl prolinate esterswith >8 C atoms; non-ionic surfactants, e.g. lauryl ether, esters ofpolyoxyethylene; ethosome (phospholipids vesicle)dimethyl(arylimino)sulfurane; mixture from oil acid analogs andpropylene glycol; mixture of Padimate O, octyl salicylate, octylmethoxycinnamate, laurocapram; highly dispersive silicon dioxide(Aerosil®); polyoxyethylene 7-glycerol monococoate (Cetiol® HE); 2-octyldodecanol (Eutanol® G), or a mixture of individual components can beused.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the lamination of the cover layer (3). comprising apolymer, channel-forming agents, and absorbing agents onto the laminatecontaining the self-adhesive matrix (2) and the removable protectivelayer (1). The laminate pulled off a reel (6) and applied onto thelaminate by means of the laminating roller (7).

FIG. 2 shows the application of the mixture (5) comprising a polymer,channel-forming agents, and absorbing agents, with a roller applicationsystem (8) onto the top side of the cover layer (4) as well assubsequent lamination with the laminating roller (7) of the cover layer(4), which has now been partially coated with the mixture (5), onto thelaminate containing the self-adhesive matrix (2) and the removableprotective layer (1).

FIG. 3 shows the application of the mixture (5) comprising a polymer,channel-forming agents, and absorbing agents, with a roller applicationsystem (8) onto the top side of the cover layer (4), which is acomponent of the laminate, which additionally contains the self-adhesivematrix (2) and the removable protective layer (1). Once the mixture hasbeen applied, the band (9) is punched out, and the waste is removed.

FIG. 4 shows the application of the mixture (5) comprising a poclyer,channel-forming agents, and absorbing agents, with a roller applicationsystem (8) onto the bottom side of the cover layer (4) as well assubsequent lamination with the laminating roller (7) of the cover layer(4), which has now been partially coated with the mixture (5), onto thelaminate containing the self-adhesive matrix (2) and the removableprotective layer (1).

FIG. 5 shows the application of the mixture (5) comprising a polymer,channel-forming agents, and absorbing agents, with a roller applicationsystem (8) onto the outward-facing side of the removable protectivelayer (1), which is a component of the laminate, which additionallycontains the self-adhesive matrix (2) and the cover layer (4). Once themixture has been applied, the band (9) is punched out, and the waste isremoved.

FIG. 6 is a top view onto the laminate, consisting of the cover layer(3), containing at least one polymer, channel-forming agents, andabsorbing agents, the self-adhesive matrix (2) and the removableprotective layer (1) and depicts the different production steps toobtain a packaged transdermal therapeutic system. In step A, thecontours of the transdermal therapeutic system are punched out of thelaminate. Step B shows the removal of the waste. In step C, the externalcontours of the transdermal therapeutic system are punched out. Step Dshows the transdermal therapeutic system after the waste removal step. Eshows the transdermal therapeutic system with a punched-on removal aidin the package sachet (transparent view).

FIG. 7 shows a cross-section of the cover layer (3) and/or removableprotective layer (1) of a transdermal therapeutic system in accordancewith this present invention. This cover layer (3) and/or removableprotective layer (1) is formed by a polymer (16) in which theincorporated channel-forming agents form a plurality of branchedchannels (14). In addition, absorbing agent particles (15) are uniformlydistributed in the polymer.

FIG. 8 shows a cross-section through a membrane system, consisting ofthe cover layer that is impermeable to the active substances (4),partially coated with the mixture of the polymer, channel-formingagents, and absorbing agents (5), a reservoir or a reservoir layer (12)containing the active substances, a membrane (11) which is permeable tothe active substances, a pressure-sensitive adhesive (10), and astate-of-the-art removable protective layer (1).

FIG. 9 depicts a cross-section through a membrane system, consisting ofthe cover layer that is impermeable to the active substances (3)containing the channel-forming agents and absorbing agents, theconventional cover layer (4), a reservoir or a reservoir layer (12)containing the active substances, a membrane (11) which is permeable tothe active substances, a pressure-sensitive adhesive (10), and astate-of-the-art removable protective layer (1).

FIG. 10 shows a cross-section through a matrix system, consisting of thecover layer that is impermeable to the active substances (3) containingthe channel-forming agents and absorbing agents, a matrix layer (13)containing the active substances and optionally permeation-enhancingagents, a pressure-sensitive adhesive (10), and a state-of-the-artremovable protective layer (1).

FIG. 11 shows a cross-section through a matrix system, consisting of thecover layer that is impermeable to the active substances (4), which hasbeen partially coated with the mixture of polymer, channel-formingagents, and absorbing agents (5), a matrix layer (13) containing theactive substances and optionally permeation-enhancing agents, apressure-sensitive adhesive (10), and a state-of-the-art removableprotective layer (1).

EXAMPLES

This present invention shall additionally be explained in more detail inthe following examples, which are not intended to limit its scope in anymanner whatsoever.

Example 1

Manufacture of a cover layer that is impermeable to the activesubstances or removable protective layer of a transdermal therapeuticsystem in accordance with this present invention in the form of a film:

First, the components polymer, channel-forming agents, and absorbingagents are mixed at an elevated temperature, and preferably, the polymerand the channel-forming agents are premixed.

The mixture is heated to the melting point and processed to form a filmby using common (state-of-the-art) methods of the casting orblow-extrusion procedures. During processing, it may be necessary topartially or completely condition the ambient atmosphere in theproduction area (primarily reduced air humidity, reduced O₂ content),for example by using dried protective gases. After such production step,optionally, additional stretching of the films can be performed tomodify their mechanical properties and to reduce their thickness. Thisproduction step is described in state-of-the-art literature.

The film obtained in such a manner can be stored in a suitable manner.It is used to cover a pressure-sensitive active substance-containinglayer one side of which, in turn, has already been covered with aseparation-coated support material and/or a support material providedwith a separation coating. Optionally, this support material mayinitially be provided with separation-coated support materials on bothsides, in which case one carrier layer must be removed immediately priorto the installation of the above film (relamination). Furthermore, theintermediate layer may consist of several sublayers, and at least one ofthese sublayers contains active substances. In this manner, a laminateof a separation-coated film, an active substance-containing layer orlayers and a drying agent-containing layer is obtained. From thislaminate, single units are obtained by punching, cutting or by usinganother suitable method, and such units are temporarily stored undersuitable conditions or directly packaged. Again, during processing ortemporary storage, it may be necessary to partially or entirelycondition the ambient atmosphere in the production area (primarilyreduced air humidity, reduced O₂ content), for example by using driedprotective gases.

Example 2

Manufacture of a cover layer that is impermeable to the activesubstances or removable protective layer of a transdermal therapeuticsystem, wherein such layers have been coated with a polymer supportcontaining absorbing agents and channel-forming agents:

First, the components polymer, channel-forming agents, and absorbingagents are mixed at an elevated temperature, and preferably, the polymerand the channel-forming agents are premixed.

Portions of the resulting mixture are packaged for subsequent processingor processed directly. For that purpose, the mixture is applied in amolten state, e.g. in an extruder or by using other suitable mixingand/or dosing devices, the basic variations of which, for example, arealready commonly used in the application of hot melt adhesives.Afterwards, the mixture is applied, for example by means of nozzles orrollers, onto the film which already forms or will form a part of theactive substance-containing composite, in a defined quantity and/orposition. Preferably, a suitable quantity thereof will be applied ontothe cover layer that is impermeable to the active substances of anactive substance-containing composite immediately prior to manufacturingand packaging the individual units. Again, during processing ortemporary storage, it may be necessary to partially or entirelycondition the ambient atmosphere in the production area (primarilyreduced air humidity, reduced O₂ content), for example by using driedprotective gases.

Example 3

Composition of the Mixture:

Polypropylene 70 percent by weight Polyethylene Glycol 10 percent byweight Molecular Sieve 4 Å 20 percent by weight

Example 4

Composition of the Mixture:

Polypropylene 35 percent by weight Polyethylene Glycol 12 percent byweight Molecular Sieve 4 Å 53 percent by weight (Baylith ® T Powder)

Example 5

Composition of the Mixture:

Polyethylene 55 percent by weight Polyethylene Glycol 10 percent byweight Molecular Sieve 4 Å 20 percent by weight

1. A transdermal therapeutic system, wherein such system is a membranesystem with an impermeable cover layer, an active substance-containingreservoir or an active substance-containing reservoir layer, and amicroporous or semipermeable membrane, an optional pressure-sensitiveadhesive layer, and a removable protective layer, wherein the coverlayer or the protective layer or both are made from at least one polymerand an embedded absorbing agent and channel-forming agent or wherein thecover layer or the protective layer or both are a film that has beencoated with a mixture (polymer support) of at least one polymer,channel-forming agents, and absorbing agent over its entire surface orin patterns.
 2. A method for the manufacture of a transdermaltherapeutic system with a layer that is impermeable to the activesubstances and a removable protective layer, wherein a polymer supportcontaining the absorbing agent and the channel-forming agent is applied,either over the entire surface or in patterns, to the layer that isimpermeable to the active substances and/or the removable protectivelayer, and wherein the transdermal therapeutic system is a matrix systemwith a cover layer that is impermeable to the active substances, one orseveral active substance-containing self-adhesive matrix layer(s) or oneor several active substance-containing matrix layer(s) that have beencoated with a pressure-sensitive adhesive, and a removable protectivelayer, wherein the cover layer or the protective layer or both are madefrom at least one polymer and an embedded absorbing agent andchannel-forming agent or wherein the cover layer or the protective layeror both are a film that has been coated with a mixture (polymer support)of at least one polymer, at least one channel-forming agent, and atleast one absorbing agent over its entire surface or in patterns; andwherein the cover layer, the protective layer or both layers have apolymer content of 10 to 90 percent by weight, based on the total weightof the mixture of the polymer, channel-forming agents, and absorbingagents; and wherein the channel forming agents are hydrophilicsubstances wherein the content of the channel forming agent is 10 to 40percent by weight based on the total weight of the mixture of thepolymer, channel-forming agents, and absorbing agents; and wherein theabsorbing agent is selected from the group consisting of drying agents,metals, alloys, metal-coated particles, inorganic substances,ion-exchange resins, substances on the basis of carbon, in particular onthe basis of elemental carbon, elastomers, semi-metals, ceramic materialand mixtures thereof; and wherein the content of the absorbing agent isfrom 10 to 70 percent by weight based on the total weight of the mixtureof the polymer, channel-forming agents, and absorbing agents; and thetransdermal therapeutic system has one or several self-adhesive matrixlayers.
 3. The transdermal therapeutic system in accordance with claim1, wherein the cover layer or the protective layer or both have beencoated with a mixture (polymer support) consisting of at least onethermoplast, at least one channel-forming agent, and at least oneabsorbing agent.
 4. The transdermal therapeutic system in accordancewith claim 1, wherein the cover layer or the protective layer or bothhave been coated, whether in a cold or hot state, with a mixture(polymer support) consisting of (i) at least one thermally crosslinkablepolymer, at least one channel-forming agent, and at least one absorbingagent, or (ii) at least one polymer which can be crosslinked by means ofradiation, at least one channel-forming agent, and at least oneabsorbing agent, and in either case, the crosslinking has been performedthereinafter.
 5. The transdermal therapeutic system in accordance withclaim 1, wherein the film used for the cover layer that is impermeableto the active substances is coated with the mixture on its top side orbottom side or on both sides.
 6. The transdermal therapeutic system inaccordance with claim 1, wherein the film that is used for the removableprotective layer is coated with the mixture on its outward-facing side.7. The method in accordance with claim 2, wherein a transdermaltherapeutic system with one or several matrix layers is produced whichare coated with a pressure-sensitive adhesive.
 8. The transdermaltherapeutic system in accordance with claim 4, wherein the radiation isUV radiation.